Despite some advances due to the extensive work that has been done to associate genetic variants with diseases, those variants explain a small proportion of the heritability of most heritable health problems. The birth defect, oral cleft, is a good example. The recurrence risk is know to be about 30-40 fold in a subsequent sibling, but known variants explain little of that recurrence. Given the protective redundancy designed into many biologic pathways, it may be that a number of particular SNPs must be simultaneously present before this defect is expressed. Given that combination, an environmental exposure might also be important. The availability of our algorithm for simulating genomic data with realistic linkage structure provides us with a laboratory for development of new methods for assessing both GxGxG interactions and GxGxE interactions.